Download pathophysiology of cardiovascular system disorders 1

PATHOPHYSIOLOGY OF
CARDIOVASCULAR SYSTEM
DISORDERS
Mehtap KACAR KOÇAK M.D. PhD
Pathophysiologist
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Learning Objectives
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Describe to Cell adhesion molecules
Describe to injury of ischemia-reperfusion
Describe to atherosclerosis
Describe to hypertension
Ischemic heart diseases
Myocardial infarction
Heart failure
Cor pulmonale (right heart failure)
Rheumatic Heart Disease
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INTEGRATING CELLS
INTO TISSUES
• Junctions:
• Cell to cell
• Gap junction
• Tight junction
• Anchoring junction
• Cell to matrix
• Focal adhesions
• Hemidesmosomes
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• The appearance of multicellular organisms allows
specialization of cells and formation of organs.
• A special matrix, the extracellular matrix, ECM,
fills out the space between cells
• ECM also binds cells together, acts as reservoir for
growth factors and hormones, and creates an
environment in which molecules and cells can
migrate.
• By means of cell adhesion molecules, CAMs, cells
are capable of recognizing each other
• Plasma membrane receptors take care of cell-ECM
interactions
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Junctions
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Figure 3-14: Types of cell junctions
Key Junction Proteins:
Connexin, cadherins, occludin & integrins
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CELL-CELL
ADHESION MOLECULES
(NONJUNCTIONAL MECHANİSM)
• Cadherins
• Ig superfamily CAMs
• Selectins
• Integrins
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CADHERINS
• A family of Ca2+-dependent CAMs
• Ca2+ causes dimerization of Cadherins
• The binding is homophilic
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IMMUNOGLOBULİN (Ig) FAMİLY
MEMBERS:
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Include:
* ICAM-1(Intracellular adhesion molecule 1),
* ICAM-2 (Intracellular adhesion molecule 2),
* VCAM-1 (Vascular cell adhesion molecule-1)
* PECAM-1(Platelet Endothelial Cell adhesion
molecule 1)
• Structure: type 1 transmembrane glycoproteins
• containing Ig homology domains
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Expression patterns of Ig adhesion
molecules:
• IL-1 and TNF upregulate ICAM-1 and
VCAM-1 expression on endothelium.
• ICAM-2 is expressed constitutively on
the endothelial surface.
• PECAM-1 is expressed constitutively on
endothelial cells at intercellular
junctions and on leukocytes.
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Ligands of Ig adhesion molecules:
ICAM-1, ICAM-2 and VCAM-1 bind
leukocyte integrins.
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Selectins:
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Three highly homologous members:
endothelial (E), platelet (P) and leukocyte (L)
Structure: type 1 transmembrane glycoproteins
E- and P-selectins are expressed by endothelial
cells.
L-selectin is expressed by leukocytes.
P- and L-selectins are expressed constitutively.
Cytokines (IL-1 and TNF) upregulate the
transcription of E- and P-selectins.
P-selectin is stored in cytoplasmic granules and a
variety of stimuli can induce rapid translocation
to the cell surface (within seconds).
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Expression patterns of endothelial cell
adhesion molecules:
Inducible
expression
Stored in
cytoplasm
Constitutively
expressed
E-selectin
P-selectin
ICAM-2
VCAM-1
PECAM-1
ICAM-1
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(Leukocyte) integrins:
• Integrins are heterodimeric transmembrane
proteins composed of alpha and beta chains.
• Integrins provide a link between the cell
cytoskeleton and the extracellular matrix.
• Integrins are clustered in focal adhesion
complexes.
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Adhesion molecules relevant to
inflammation:
• Adhesion molecules are proteins with
structural domains that mediate the
adhesion of leukocytes to endothelial
cells.
• Adhesion molecules are proteins that
contain structural domains.
• Each adhesion molecule can bind one
or several ligands or counter-receptors.
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Leukocyte integrin ligands:
• Leukocyte integrins bind members of the Ig gene
superfamily as well as other proteins.
• Integrin
Counter-receptors
• L2
ICAM-1, ICAM-2
• (LFA-1, CD11a/CD18)
• M2
ICAM-1, fibrinogen, iC3b
• (Mac-1, CD11b/CD18)
• 41
VCAM-1, fibronectin CS-1
• (VLA-4, CD49d/CD29)
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Endothelial Cell Activation
Inflammatory cytokines (e.g., IL-1 or
TNF) activate endothelial cells to
express adhesion molecules.
Unactivated
Activated
nonadhesive
for leukocytes
hyperadhesive
for leukocytes
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Integrin activation during
inflammation
NORMAL
INFLAMMATION
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Leukocyte adhesion cascade
A sequence of activation and adhesion events
leading to the extravasation of leukocytes at
the site of inflammation.
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Capture and Rolling (Fast-slow)-Selectins
Firm Adhesion-Integrins
Transmigration
Block in any one of them greatly reduces
leukocyte accummulation in the damaged
tissue.
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Leukocyte Adhesion Cascade.
Capture and Rolling
• Cytokines released by injury activate venular endothelial
cells and induce them to express P-selectin (stored in
Weibel-Palade bodies) on their surface which interacts
with a glycoprotein on leukocytes.
• As a result the leukocytes roll along the endothelium
forming bonds at the leading edge and breaking them at
the trailing one.
• L-selectin expressed by leukocytes also participates in the
rolling process. It may be necessary for the initial
attachment to the endothelium. In absence of P-selectin
rolling is less efficiently mediated by L-selectin.
• E-selectin expressed by activated endothelial cells is
required to slow down rolling of leukocytes and initiates
stronger adhesion.
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General mechanism of cell
injury
• The three common forms of cell injury are;
• 1- hypoxic injury (and following
reperfusion injury)
• 2- reactive oxygen species (ROS) and free
radical-induced injury
• 3- chemical injury (CCl4)
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ISCHEMIA - REPERFUSION
INJURY
• Hypoxia, or lack of sufficient oxygen, is the
single most common cause of cellular injury.
• Hypoxia can result from:
• a decreased amount of oxygen in the air ,
• loss of Hb or Hb function,
• decreased production of red blood cells,
• diseases of the respiratory and cardiovascular
system,
• poisoning of the oxidative enzymes
(cytochromes) within the cells.
• The most common cause of hypoxia is ischemia
(reduced blood supply).
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• Ischemic injury is often caused by gradual
narrowing of arteries (arteriosclerosis),
and complete blockage by blood clots
(thrombosis).
• Cellular responses to hypoxic injury have
been extensively studied in heart muscle.
• Within 1 minute after blood supply to the
myocardium is interrupted, the heart
becomes pale.
• Within 3 to 5 minutes, the ischemic
portion of the myocardium ceases to
contract.
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• The abrupt lack of contraction is caused
by a rapid decrease in mitochondrial
phosphorylation, which results in
insufficient ATP production.
• Lack of ATP leads to an increase in
anaerobic metabolism, which generates
ATP from glycogen when there is
insufficient oxygen.
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Irreversible damage characterized by
two events:
• 1- lack of ATP generation because of
mitochondrial dysfunction,
• 2- major disturbances and damage in membrane
function.
• Acid hydrolases from leaking lysosomes are
activated in the reduced pH of the injured cell and
they digest cytoplasmic and nuclear components.
• Leakage of intracellular enzymes into the
peripheral circulation provides a diagnostic tool
for detecting tissue-specific cellular injury and
death using blood samples (troponin-MI, liver
transaminases-hepatic injury)
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Reperfusion injury
• Restoration of oxygen, however, can cause
additional injury called reperfusion injury.
• Xanthine dehydrogenase, an enzyme which
normally utilizes oxidized nicotinamide
adenine dinucleotid (NAD+) as an electron
acceptor, is converted during reperfusion
with oxygen to xanthine oxidase.
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• During ischemic period, excessive ATP
consumption leads to the accumulation of
the purine catabolites hypoxanthine and
xanthine ;
• Which upon subsequent reperfusion and
influx of oxygen are metabolized by
xanthine oxidase to make massive
amounts of superoxide and hydrogen
peroxide.
• In addition the highly reactive free radical
nitric oxide is generated.
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• These radicals can all cause membrane
damage and mitochondrial calcium
overload.
• Neutrophils are especially affected
with reperfusion injury, and
neutrophil adhesion to the
endothelium enhances the process.
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Free radicals and reactive oxygen
species-induced injury
• An important mechanism of membrane damage is
injury induced by free radicals, especially ROS
called oxidative stress.
• Oxidative stress occurs when excess ROS
overwhelms endogenous antioxidant systems.
• Free radicals may be initiated within cells by :
• 1- the absorption of extreme enerjy sources (UV,
x-ray)
• 2- endogenous (during normal metabolic process)
• 3- enzymatic metabolismof exogenous chemicals
or drug.
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• Free radicals and ROS, three are
particularly important in regard to cell
injury:
• 1- lipid peroxidation
• 2- alterations of proteins causing
fragmentation of polypeptide chains,
• 3- alterations DNA, including breakage of
single strands..
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CARDIOVASCULAR
DISORDERS: Vascular Disease
• Outlines:
• Pathophysiology of Atherosclerosis
• Pathophysiology of Hypertension
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Arteriosclerosis
• Arteriosclerosis is a chronic disease of
arterial system characterized by abnormal
thickening and hardening of the vessel
walls.
• In arteriosclerosis the tunica intima
undergoes a series of changes that decrease
the artery’s ability to change lumen size.
• Smooth muscle cells and collagen fibers
migrate into the tunica intima, causing it to
stiffen and thicken.
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Arteriosclerosis:
Pathophysiology
• General term for all
types of arterial
changes
• Best for degeneration
in small arteries and
arterioles
• Loss of elasticity,
walls thick and hard,
lumen narrows
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Atherosclerosis
• Atherosclerosis is a form of
arteriosclerosis in which the thickening
and hardening of the vessel is caused
by the accumulation of lipid-laden
macrophages within the arterial wall,
which leads to the formation of a lesion
called plaque.
• It is leading contributor to coronary
artery and cerebrovascular disease.
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Atherosclerosis:
Pathophysiology
• Presence of atheromas
• Plaques
• Consist of lipids, cells, fibrin,
cell debris
• Lipids usually
transported with
lipoproteins
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Consequences of Atherosclerosis
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Lipoproteins and Transport
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Atherosclerosis--Diagnosis
• Analysis of serum lipids:
• Total cholesterol, triglycerides, LDL, HDL
• LDL
• High cholesterol content
• Transports cholesterol liver  cells
• Dangerous component
• HDL
• “good”
• Low cholesterol content
• Transports cholesterol cells  liver
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Atherosclerosis—Risk Factors
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Age
Gender (Male)
Genetic factors
Obesity, diet high in cholesterol,
animal fats
Cigarette smoking
Sedentary life style
Diabetes mellitus
Poorly controlled hypertension
Smoking
•LDL↑
•HDL↓
•hyperhomocystinemia
•CRP ↑
•Serum fibrinogen ↑
•Oxidative stress
•Peridontal disease
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Pathophysiology of
atherosclerosis
• Atherosclerosis is an inflammatory disease.
• Atherosclerosis begins with injury to the
endothelial cells that line artery walls. (Risk
factors!!!) (remember leukocyte adhesion)
• Pathologically the lesions progress from:
endothelial injury and dysfunction to fatty
streak to
• fibrotic plaque to
• complicated lesions.
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• Once injury has occured, endothelial
dysfunction and inflammation lead to the
following events:
• 1. injured ECs become inflamed and
cannot make normal amounts of
antithrombotic and vasodilating
cytokines.
• 2. numerous inflammatory cytokines are
released, including TNF-α, IF-γ, IL-1,
toxic oxygen radicals, and heat shock
proteins.
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• 3. growth factors are also released,
including AngII, FGF, PDGF, which
stimulate smooth muscle cell proliferation
in the affected vessels.
• 4. macrophages adhere to injured
endothelium by way of adhesion molecules
such as VCAM-1.
• 5. these macrophages then release enzymes
and toxic oxygen radicals that create
oxidative stress, oxidize LDL, and further
injure the vessel wall.
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• The oxidation of LDL is an important step in
atherogenesis. (smoking, diabetes, hypertension…)
• Inflammation with oxidative stress and activation
of macrophages is the primary mechanism.
• The oxidized LDL penetrates into the intima of the
arterial wall and is engulfed by macrophages.
Macrophages filled with oxidized LDL are called
foam cells.
• Once these lipid-laden foam cells accumulate in
significant amounts, they form a lesion called a
fatty streak.
• At this point SMCs proliferate, produce collagen,
and migrate over the fatty streak forming a fibrous
plaque.
• Plaques that have ruptured are called complicated
plaques.
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Clinical manifestations of
atherosclerosis
• Coronary artery disease (CAD) (major
cause of myocardial ischemia)
• Stroke
• Hypertension
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HYPERTENSION
• Hypertension is defined as a sustained
elevation of systemic arterial blood
pressure.
• Hypertension is caused by increases in
cardiac output, total peripheral
resistance, or both.
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Classification of hypertension
• Primary hypertension (essential or
idiopathic hypertension): most cases of
combined systolic and diastolic
hypertension have no known cause and are
diagnosed as primary hypertension. This
type affects 90% to 95% of hypertensive
individuals.
• Secondary hypertension: It is caused by
altered hemodynamics associated with a
primary disease, such as renal disease. (5%to
8% of cases)
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Classification of hypertension
• Isolated systolic hypertension: It is
elevated SBP accompained by normal
DBP. This type is a manifestation of
increased cardiac output or rigidity of
the aorta or both.
• Malignant hypertension (rapidly
progressive hypertension in which
diastolic pressure is usually above 140
mmHg) can cause encephalopathy,
cerebral edema.
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Factors associated with primer
hypertension
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Family history of hypertension,
Advancing age,
Gender (male),
Black race,
High dietary sodium intake,
Glucose intolerance (diabetes mellitus),
Smoking,
Obesity,
Heavy alcohol consumption,
Low dietary intake of potassium, calcium, magnesium.
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Pathophysiology of primary
hypertension
• Primary hypertension is the result of a complicated
interaction between genetics and environment and their
effects on vascular and renal function.
• Multiple pathophysiologic mechanism mediate these
effects including the sympathetic nervous system (SNS),
the renin-angiotensin-aldosterone system (RAA),
adductin, and natriuretic peptides.
• Inflammation, endothelial dysfunction and insulin
resistance also contribute to both increased peripheral
resistance and increased blood volume.
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• In the healty indivudial, the Symphatetic
NS contributes to the maintenance of
adequate blood pressure and tissue
perfusion
• by promoting cardiac contractility and
heart rate (maintenance of adequate cardiac
output) and,
• by inducing arteriolar vasoconstruction
(maintenance of adequate peripheral
resistance).
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• In indivudials with hypertension, overactivity of the SNS can result from increased
productionof catecholamines (E, NE) or from
increased receptor activity involving these
neurotransmitters.
• Increased SNS activity causes heart rate and
systemic vasoconstruction, thus raising the
blood pressure.
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• Dysfunction of the RAA system in the
hypertensive indivudual can lead to persistent
increases in peripheral resistance and renal salt
retention.
• Angiotensin II also causes structural changes in
blood vessels (remodeling) that contribute to
permanent increases in peripheral resistance and
make vessels more vulnerable to endothelial
dysfunction and platelet aggregation.
• Angiotensin II is also responsible for the
hypertrophy of the myocardium associated with
hypertension.
• Aldosterone not only contributes to sodium
retention by the kidney but also has further
deleterious effects on the cardiovascular system.
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• Natriuretic hormones modulate renal sodium
excretion and include;
• Atrial natriuretic peptide (ANP),
• Brain natriuretic peptide (BNP),
• C-type natriuretic peptide (CNP),
• Urodilanton.
• The function of these hormones can be effected
by excessive sodium intake; inadequate dietary
intake of K, Mg, Ca and obesity.
• Therefore; salt retention leads to water retention
and increased blood volume, which contributes
to an increasein blood pressure.
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• Inflammation plays a role in the
pathogenesis of hypertension.
• Endothelial injury and tissue ischemia result
in the release of vasoactive inflammatory
cytokines.
• Endothelial dysfunction in primary
hypertension is characterized by
• a decreased production of vasodilators, such
as nitric oxide, and
• increased production of vasoconstructors,
such as endothelin.
• Insulin resistance is associated with
endothelial dysfunction in primary
hypertension even without overt diabetes.
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• Diabetes and insuline resistance also
cause changes in SNS and RAA activity,
cause renal glomerular dysfunction and
contributeto the target organ effects.
• Primary hypertension is the result of an
interaction between many of the abovedescribes processes.
• The majority of these factors influence
renal sodium excretion and shift the
pressure-natriuresis relationship.
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Secondary hypertension
• Secondary hypertension is caused by a
systemic disease process that raises
peripheral vascular resistance or
cardiac output.
• If the cause is identified and removed
before permanent structural changes
occur, blood pressure returns to
normal.
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Isolated systolic hypertension
• Elevations of systolic pressure are
caused by increases in cardiac output or
total peripheral vascular resistance or
both.
• For example; aortic valve insufficiency,
arterioventricular fistula, thyrotoxic
crisis, paget disease of the bone and
beriberi.
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Complicated hypertension
• Chronic hypertension damages the
walls of systemic blood vessels.
• Within the walls of arteries and
arterioles, smooth muscle cells
undergo hypertrophy and hyperplasia
with associated fibrosis of the tunica
intima and media in a process called
“vascular remodeling” .
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• Endothelial dysfunction, angiotensin
II, catecholamines, insulin resistance,
and inflammation all contribute this
process.
• Once significant fibrosis has occured,
reduced blood flow and dysfunction
of the organs perfused by these
affected vessels is inevitable.
• Target organs for hypertension include
the kidney, brain, heart, extremities
and eyes.
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Clinical manifestations of
hypertension
• The early stages of hypertension have no
clinical manifestations other than elevated
blood pressure.
• Most important no signs and symptoms
cause the individual to seek health care;
thus hypertension is called a lanthanic
(silent) disease.
• Initial signs vague, nonspecific
• Fatigue, malaise, morning headache
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Coronary Artery Disease,
Myocardial Ischemia
• Coronary artery disease (CAD) is a
condition in which the blood supply to
the heart muscle is partially or
completely blocked.
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•CAD is almost always due to the build-up of
cholesterol and other fatty materials (called
atheromas or atherosclerotic plaques) in the
wall of a coronary artery.
•Occasionally CAD results from a spasm of an
artery, and rarely, the cause is a birth defect, or
an infection leading to inflammation of the
arteries (arteritis), or physical damage (from an
injury or radiation therapy).
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• CAD is the most common cause of myocardial
ischemia. The major complications of coronary
artery disease are chest pain due to myocardial
ischemia (angina) and heart attack (myocardial
infarction).
• CAD is the most common type of cardiovascular
disease, occurring in about 5 to 9% of people
aged 20 and older. The death rate increases with
age and overall is higher for men than for
women. After age 55, the death rate for men
declines, and the rate for women continues to
climb. After age 70 to 75, the death rate for
women exceeds that for men who are the same
age.
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Risk factors of CAD
• A- Nonmodifiable (major) risk factors:
• 1- Advanced age
• 2- Male gender or woman after
menopause,
• 3- Family history (Genetics)
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Risk factors of CAD
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B- Modifiable risk factors:
1- Dyslipidemia,
2- Hypertension
3- Cigarette smoking,
4- Diabetes and insulin resistance,
5- Obesity,
6- Sedentary life-style,
7- Atherogenic diet.
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Risk factors of CAD
• C- Novel risk factors:
• 1- Markers of inflammation and
thrombosis,
• 2- Hyperhomocysteinemia,
• 3- Infection.
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Dyslipidemia and CAD
• The strong link between CAD and elevated
plasma Lipoprotein concentrations (lipids,
phospholipids, cholesterol, and
triglycerides) is well documented.
• Dyslipidemia refers to abnormal
concentrations of serum lipoproteins.
These abnormalities are the result of a
combination of genetic and dietary factors.
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Criteria for dyslipidemia
Optimal
Near
optimal
Total
cholesterol
LDL
Triglycerides
HDL
Desirable
Low
< 200
<100
100-129
<150
<40
Borderline
High
Very
High
200-239
≥240
130-159
160189
≥190
150-199
200499
≥500
≥60
Data from expert panel on detection, eveluation, and treatment of high blood cholesterol in adults, 88
JAMA 285:2486-2497, 2001)
• Primary or familial dyslipoproteinemias
result from genetic defects that cause
abnormalities in lipid-metabolizing
enzymes and abnormal cellular lipid
receptors.
• Secondary causes of dyslipidemia
include several common systemic
disorders such as diabetes,
hypothyroidism, pancreatitis and renal
nephrosis.
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• An increased levels of LDL is a strong indicator
of coronary risk.
• (remember to atherosclerosis!!!)
• Low levels of HDL also are strong indicator of
coronary risk, and high levels of HDL may be
more protective for the development of
atherosclerosis than low levels of LDL.
• HDL responsible for “reverse cholesterol
transport”, which returns excess cholesterol from
into the tissues to the liver for metabolism.
• HDL also participate in endotheial repair and
decreases thrombosis.
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• Exercise, weight loss, fish oil
consumption can result in modest
increases in HDL.
• Niacin, fibrates, and statins are drugs that
can cause modest increases in HDL.
• Other lipoproteins associated with
increased cardiovascular risk include
elevated serum VLDL (triglycerides) and
lipoprotein (a).
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Hypertension and CAD
• Hypertension is responsible for a twofold
to threefold increased risk of
atherosclerotic cardiovascular disease.
• A reduction in systolic blood pressure of
only 12-13 mmHg can reduce the risk of
CAD by as much as 21%.
• It contributes to endothelial injury a key
step in atherogenesis and causes
myocardial hypertrophy, which increases
myocardial demand for coronary flow.
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Smoking and CAD
• Studies indicate that 20% of the annual mortality
from CAD is traceable to cigarette smoking.
• Nicotine stimulates the release of catecholamines
(E, NE), which increase heart rate and peripheral
vascular constriction. As a result, blood pressure
increases, as do cardiac workload and oxygen
demand. Elevated catecholamines also stimulated
release of free fatty acids.
• Cigarette smoking is associated with an increase in
LDL, a decrease in HDL, an induction of a
prothrombotic state, as well as increases in
inflammatory markers of CAD such as CRP and
fibrinogen.
• After smoking is disconytinued, the risk associated
with CAD may decrease as much as 50% in 1 year.
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Diabetes mellitus and CAD
• DM is an extremely important risk factor for
CAD.
• DM is associated with a two fold increase in the
risk for CAD death and up to a sixfold risk for
stroke.
• Diabetes and insulin resistance have multiple
effects on the cardiovascular system throıgh the
production of toxic ROS taht alter vascular cell
function.
• These effects can include endothelial damage,
thickening of the vessel wall, increased
inflammation and leukocyte adhesion, increased
thrombosis, glycation of vascular proteins, and
decreased production of endothelial-derived 95
vasodilators such as nitric oxide.
Obesity and CAD
• Obesity is caused by genetics, diet and
inadequate physical exercise.
• Abdominal obesity has the strongest link
with increased CAD risk and is related
to insulin resistance, decreased HDL,
increased blood pressure.
• A sedentary life-style not only increases
the risk of obesity but also has an
independent effect on increasing CAD
risk.
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Markers of inflammation and
thrombosis and CAD
• CRP is an indirect measure of
atherosclerotic plaque; related
inflammation and is an important indicator
of CAD risk.
• Elevated levels of CRP are associated with
CAD.
• Other markers of inflammation associated
with CAD include the erytrocyte
sedimentation rate, von Willebrand factor
concentration, IL-6, IL-18, fibrinogen.
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Hyperhomocysteinemia and
CAD
• Hyperhomocysteinemia occurs because of a
genetic lack of the enzyme that break down
homocysteine (an amino acid) or because of
nutritional deficiency of folate, cobalamin (vit
B12), or pyridoxine (vit B6).
• Mechanism by which it contributes to coronary
disease include associated increases in LDL,
decreases in endogenous vasodilators, and an
increased tendency for thrombosis.
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Infection and CAD
• Emerging is evidence that infection may play
role in atherogenesis and CAD risk.
• Studies have found that several
microorganisms, especially Chlamydia
pneumonae, and Helicobacter pylori are often
present in atherosclerotic lesions.
• Serum antibodies to microorganisms have been
linked to an increased risk for CAD as has the
presence of periodontal disease.
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Myocardial ischemia
• The coronary arteries normally supply
blood flow sufficient to meet demands
of the myocardium as it labors under
varying workloads.
• Oxygen extraction from these vessels
occurs with maximal efficiency.
• If efficient exchange meet myocardial
oxygen needs, healthy coronary arteries
are able to dilate to increase the flow of
oxygenated blood to the myocardium. 100
• Myocardial ischemia develops if the
supply of coronary blood cannot meet
the demand of the myocardium for
oxygens and nutrients.
• Imbalances between coronary blood
supply and myocardial demand can
result from a number of conditions.
• The most common cause of decreased
coronary blood flow and resultant
myocardial ischemia is the formation of
atherosclerotic plaques in the coronary
circulation.
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• As the plaque increases in size, it may partially
occlude vessel lamina, thus limiting coronary
flow and causing ischemia especially during
exercise.
• Some plaques are “unsatble”, meaning they are
prone to ulceration or rupture.
• When this occurs, underlying tissues of the
vessel wall are exposed resulting in platelet
adhesion and thrombus formation.
• This can suddenly cut off blood supply to the
heart muscle resulting in acute myocardial
ischemia and, if the vessel obstruction cannot be
reversed rapidly, ischemia progress to
infarction.
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• Myocardial ischemia also can result
from other causes of decreased blood
and oxygen delivery to the
myocardium, such as coronary spasm,
hypotension, arrhythmias, and
decreased oxygen-carrying capacity of
the blood (anemia, hypoxemia).
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• Myocardial cells become ischemic within 10
seconds of coronary oclusion.
• After several minutes the heart cells lose the
ability to contract, and cardiac output
decreases.
• Ischemia also causes conduction
abnormalities that lead to chnages in the
electrocardiogram and may initiate
dysrhythmias.
• Anaerobic processes take over, and lactic acid
accumulates.
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• Cardiac cells remain viable for
approximately 20 min under ischemic
conditions.
• If blood flow is restored, aerobic metabolism
resumes, contractility is restored and
cellular repair begins.
• If perfusion is not restored within 40-60 min,
an irreversible stage of injury characterized
by diffuse mitochondrial swelling, damage
to cell membrane and marked depletion of
glycogen begins.
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Clinical manifestations of
myocardial ischemia
• Stable angina,
• Prinzmetal angina,
• Silent ischemia and mental stress
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Stable angina
• Chronic coronary obstruction result in
recurrent predictable chest pain called stable
angina.
• Angina pectoris is chest pain caused by
myocardial ischemia.
• The discomfort is usually transient lasting
approximately 3 to 5 minutes.
• Angina pectoris is typically experienced as
substernal chest discomfort, ranging from a
sensation of heaviness or pressure to
moderately severe pain.
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• The pain is presumably caused by the buildup
of lactic acid or abnormal stretching of the
ischemic myocardium that irritates myocardial
nerve fibers.
• Pallor, diaphoresis, and dyspnea may be
associated with the pain.
• Stable angina is caused by gradual luminal
narrowing and hardening of the arterial walls,
so affected vessels cannot dilate in response to
increased myocardial demand associated with
physical exertion ar emotional stress.
• The pain is usually relieved by rest and
nitrates.
108
Prinzmetal angina
• Prinzmetal angina is chest pain
attributable to transient ischemia of the
myocardium that occurs unpredictably
and almost exclusively at rest.
• Pain is caused by vasospasm of one or
more major coronary arteries with or
without associated atherosclerosis.
• The pain often occurs at night during
rapid eye movement sleep and may
have a cyclic pattern of occurence.
109
Silent ischemia
• Myocardial ischemia often does not cause detectable
symptoms such as angina. Ischemia can be totally
asymptomatic and referred to as silent ischemia.
• Another area that receiving renewed interest is the lack of
angina even though an artery is occluded, in some
individuals during mental stress.
• The increases in blood pressure induced by mental stress
and increases in myocardial oxygen demand may play role
in the pathophysiology of myocardial ischemia induced by
mental stress.
• Chronic stress has been linked to a hypercoagulable state
that may contribute to acute ischemic events.
110
111
112
Clinical manifestations and
evaluation
• Physical examination may disclose extra,
rapid heart sounds (S3).
• The presence of xanthelasmas (small fat
deposits) around the eyelids or arcus senilis
of the eyes ( a yellow lipid ring around the
cornea) suggest dyslipidemia and possible
atherosclerosis.
• ECG,
• Coronary angiography,
• SPECT (single-photon emission computed
tomography)
113
114
Acute Coronary Syndromes:
• Unstable angina,
• Myocardial infarction
115
116
Unstable angina
• Unstable angina is a form of acute coronary
syndrome that result in reversible myocardial
ischemia.
• A fairly small fissuring or superficial erosions
of the plaque leads to transient episodes of
thrombotic vessels occlusion and
vasoconstruction at the site of plaque
damage.
• This thrombus is labile, and occludes the
vessel for no more than 10 to 20 min, with
return of perfusion before significant
myocardial necrosis occurs.
117
118
Clinical manifestations of
unstable angina
• Unstable angina presents as new onset
angina, angina that is occuring at rest, or
angina that increasing in severity or
frequency.
• Physical examination may reveal
evidence of ischemic myocardial
dysfunction such as tachycardia, S3 gallop,
or pulmonary congestion.
119
120
Myocardial infarction (MI)
• When coronary blood flow is
interrupted for an extended period of
time, myocyte necrosis occurs. This
results in myocardial infarction.
• Pathologically there are two major
types of MI;
• * subendocardial infarction,
• * transmural infarction.
121
• Coronary artery completely obstructed
• Prolonged ischemia and cell death of myocardium
• Most common cause is atherosclerosis with
thrombus
• 3 ways it may develop:
• Thrombus obstructs artery
• Vasospasm due to partial occlusion
• Embolus blocks small branch of coronary artery
• Majority involve Left ventricle
• Size and location of infarction determine severity
of damage
122
• Function of myocardium contraction
and conduction quickly lost
• Oxygen supplies depleted
• 1st 20 minutes critical
• Time Line
• 1st 20 min critical
• 48 hrs inflammation begins to subside
• 7th day necrosis area replaced by fibrous
tissue
• 6-8 weeks scar forms
123
Pathophysiologic changes in MI
• 1- cellular ınjury,
• 2- cellular death,
• 3- structural and functional changes,
• 4- repair
124
Cellular injury
• Cardiac cells can withstand ischemic conditions
for about 20 minutes before cellular death take
place.
• After only 30 to 60 second of hypoxia, ECG
changes are visible.
• After 8 to 10 seconds of decreased blood flow, the
affected myocardium becomes cyanotic and
cooler.
• Myocardial oxygen reserves are used very quickly
(about 8 s) after complete cessation of coronary
flow.
• Glycogen stores decrease and anaerobic
metabolism begins.
125
• Glycolysis can supply only 65% to 70% of
the total myocardial energy requirement
and produces much less ATP than aerobic
process.
• Hidrogen ions and lactic acid accumulate.
• Oxygen deprivation also is accompained by
electrolyte disturbances, spesifically loss of
potassium, calcium and magnesium from
cells.
• Myocardial cells deprived of necessary
oxygen and nutrients lose contractility,
thereby diminishing the pumping ability
of the heart.
126
• Normally, the myocardium takes up varying
quantities of catecholamines.
• Significant arterial occlusioncauses the myocardial
cells to release catecholamines, predisposing the
individual to serious imbalances of sympathetic
and parasympathetic function, irregular heartbeats
(dysrhythmia) and heart failure.
• Catecholamines mediate the release of glycogen,
glucose and stored fat fom body cells.
• Therefore plasma concentrations of free fatty acids
and glycerol rise within 1 hour after onset of acute
MI.
• Excessive levels of free fatty acids can have a
harmful detergent effects on cell membranes.
• NE elevates blood sugar levels through stimulation
of liver and skeletal muscle cells. (hyperglycemia is
noted 72 hours after an acute MI)
127
• Angiotensin II is released during myocardial
ischemia and contributes to the pathogenesis of MI
in several ways.
• It result in the systemic effects of peripheral
vasoconstruction and fluid retention.
• These hemostatic responses are counterproductive in that they increase myocardial work
and thus exacerbate the effects of the loss of
myocyte contractility.
• AngII is also released locally, where it is a growth
factor for VSMC, myocytes and cardiac fibroblasts;
promote catecholamines release; and causes
coronary artery spasm.
128
Cellular death
• After about 20 min of myocardial ischemia,
irreversible hypoxic injury causes cellular
death and tissue necrosis.
• Necrosis of myocardial tissue result in the
release of certain enzymes through the
damaged cell membranes into the
interstitial spaces.
• The lymphatics pick up the enzymes and
transport them into the bloodstream, where
they can be detected by serologic tests.
129
Structural and functioanl changes
130
• The severity of functional impairment depends on
the size of the lesion and the site of infarction.
• Functional changes can include:
• 1- decreased cardiac contractility with abnormal
wall motion,
• 2- altered left ventricular compliance,
• 3-decreased stroke volume,
• 4- decreased ejection fraction,
• 5- increased left ventricular end-systolic pressure,
• 6- SA node malfunction.
• Life-threatening dysrhythmias and heart failure
often follow MI
131
Repair
• MI causes a severe inflammatory response that ends
with wound repair.
• Repair consists of degradation of damaged cells,
proliferation of fibroblasts, and synthesis of scar
tissue.
• Within 24 hours leukocytes infiltrate the necrotic
area and proteolytic enzymes from scavenger
neutrophils degrade necrotic tissue.
• By the second week insulin secretion increases to
mobilize glucose from the repair process.
• After 6 weeks the necrotic area is completely
replaced by scar tissue, which is strong but unable
to contract and relax like healty myocardial tissue.
132
MI: signs and symptoms
• Pain
• Sudden, substernal area
• Radiates to left arm and neck
• Less severe in females
• Pallor, sweating, nausea, dizziness (vasovagal
reflexs and catecholamines release)
• Anxiety and fear
• Hypotension, rapid and weak pulse (low
Cardiac Output)
• Low grade fever
133
MI—Diagnostic Tests
• ECG
• Serum enzyme and
isoenzyme test
• High serum levels of
myosin and troponin
• Abnormal electrolytes
• Leukocytosis
• Arterial blood gases
• Pulmonary artery
pressure measure
• Determines ventricular
function
134
MI—Complications
• Arrhythmias
• 25% pts sudden death after MI
• Due to ventricular arrhythmias and fibrillation
• Heart block
• Premature ventricular contraction (PVCs)
• Cardiogenic shock
• CHF
135
Heart Failure
• Heart failure is a disorder in which the heart
pumps blood inadequately, leading to reduced
blood flow, back-up (congestion) of blood in the
veins and lungs, and other changes that may
further weaken the heart.
136
CHF—Etiology
• Increased demands on heart cause
failure
• Depends on ventricle most adversely
affected
• Ex: Hypertension increases diastolic bp
• Requires L ventricle to contract more forcibly to
open aortic valve
• Ex: Pulmonary disease
• Damages lung caps, increases pulm resistance
• Increase work load to R vent
137
CHF—Etiology
• Causes of failure on affected side:
• Infarction that impairs pumping ability or
efficiency of conduction system
• Valve defects
• Congenital heart defects
• Coronary artery disease
138
classification
• 1- congestive heart failure (left heart
failure),
• 2- right heart failure,
• 3- high-output failure
139
congestive heart failure
(left heart failure),
• Congestive heart failure, is categorized
as a systolic heart failure or diastolic
heart failure.
140
141
Left Heart Failure
Systolic Dysfunction: Disorders that cause
systolic dysfunction may impair the entire heart
or one area of the heart. As a result, the heart
does not contract normally. Coronary artery
disease is a common cause of systolic
dysfunction. It can impair large areas of heart
muscle because it can reduce blood flow to
large areas of heart muscle.
Diastolic Dysfunction: Inadequately treated
high blood pressure is the most common cause
of diastolic dysfunction. High blood pressure
stresses the heart because the heart must
pump blood more forcefully than normal to force
blood into the arteries against the higher
pressure. Eventually, the heart's walls thicken
(hypertrophy), then stiffen. The stiff heart does
not fill quickly or adequately, so that with each
contraction, the heart pumps less blood than it
normally does.
142
• In systolic dysfunction, the heart contracts
less forcefully and cannot pump out as
much of the blood that is returned to it as it
normally does. As a result, more blood
remains in the lower chambers of the heart
(ventricles). Blood then accumulates in the
veins.
• Cardiac output depends on heart rate and
stroke volume.
• Stroke volume is influenced by three major
factor; contractility, preload, afterload.
143
• In diastolic dysfunction, the heart is stiff
and does not relax normally after
contracting. Even though it may be able
to pump a normal amount of blood out
of the ventricles, the stiff heart does not
allow as much blood to enter its
chambers from the veins. As in systolic
dysfunction, the blood returning to the
heart then accumulates in the veins.
Often, both forms of heart failure occur
together.
144
145
146
147
148
Mechanisms and Examples that Cause Left Sided
Heart Failure
Impaired Contractility
Increased Afterload
(Pressure Overload)
1. Myocardial
infarction
1. Aortic Stenosis
2. Transient myocardial
ischaemia
2. Uncontrolled
hypertension
3. Chronic volume overload
a. Mitral regurgitation
b aortic regurgitation
Systolic
Dysfunction
4. Dilated cardiomyopathy
Left-sided
Heart Failure
Impaired Ventricular
Relaxation
Diastolic
Dysfunction
Increased Afterload
(Pressure Overload)
1. Left ventricular hypertophy
1. Mitral Stenosis
2. Hypertrophic cardiomyopathy
2. Pericardial constriction or
3. Restrictive cardiomyopathy
tamponade
4, Transient myocardial ischaemia
149
150
Right ventricular failure
• RVF can result from left HF when the
increase in left ventricular filling
pressure that is reflected back into the
pulmonary circulation is severe enough.
• As pressure in the pulmonary
circulation rises, the resistance to right
ventricular emptying increases.
• The right ventricle is poorly prepared to
compensate for this increased workload
and will dilate and fail.
151
152
• COR PULMONALE:
• When RHF happens, pressure will rise in
the systemic venous circulation, resulting
in peripheral edema and
hepatosplenomegaly.
• When RHF occurs in the absence of LHF, it
is caused most commonly by diffuse
hypoxic pulmonary disases (COPD, ARDS,
cystic fibrosis), and this type of right
ventricular dysfunction is called
“COR PULMONALE”.
153
154
High-output heart failure
• High-output failure is the inability of the
heart to adequately supply the body with
blood-borne nutrients, despite adequate
blood volume and normal or elevated
myocardial contractility.
• In high-output failure the heart increases its
output but the body’s metabolic needs are
still not meet.
• Common causes of high-output failure are
anemia, septicemia, hyperthyroidism and
beriberi.
155
156
CHF—Signs and Symptoms
• Forward effects
• Similar with failure on either side
• Decrease blood supply to tissue and general
hypoxia
• Fatigue, weakness, dyspnea (breathlessness),
cold intolerance, dizziness
• Compensation mechanism
• Indicated by tachycardia, pallor, daytime
oliguira
157
CHF—Signs and Symptoms
• Systemic backup effects of R-sided failure
• Edema in feet, legs
• Hepatomegaly, splenomegaly
• Ascites
• Acute R-sided failure
• Increased pressure on SVC
• Flushed face, distended neck veins, headaches, vision
problems
158
CHF—Diagnostic Tests
• Radiographs
• Catheterization
• Arterial blood gases
159
Diagnostic Tests for
Cardiovascular Function
• ECG
• Monitors arrhythmias, MI, infection, pericarditis
• Studies conduction activation and systemic abnormalities
• Ausculation
• Studies heart sounds using stethoscope
• Exercise stress test
• Assess general cardiovascular function
• Checks for exercise-induced problems
• Chest X-ray Film
• Shows shape, size of heart
• Evidence of pulmonary congestion associated with heart failure
• Nuclear imaging
160
Diagnostic Tests
• Cardiac
Catheterization
• Visualize inside of
heart, measure
pressure, assess valve
and heart function
• Determine blood flow
to and from heart
161
Diagnostic Tests
• Angiography
• Visualization of blood
flow in coronary
artery
• Obstruction assessed
and treated
• Basic catheterization
• Balloon angioplasty
162
Diagnostic Tests
• Doppler Studies
• Assessment of blood flow in peripheral vessels
• Microphone records sounds of blood flow
• Can detect obstruction
• Blood tests
• Assess triglyceride and cholesterol levels
• Electrolytes
• Hb, hematocrit, cbcs
• Arterial Blood Gas Determination
• Essential for pts with shock, MI
• Check current oxygen levels, acid-base balance
163
General Treatment Measures
for Cardiac Disorders
• Dietary modification
• Regular exercise program
• Quit smoking
• Drug therapy
164
ACUTE RHEUMATIC FEVER
• Autoimmune consequence of
infection with Group A streptococcal
infection
• Results in a generalised
inflammatory response affecting
brains, joints, skin, subcutaneous
tissues and the heart.
165
• RF is a delayed autoimmune response to
Group A streptococcal pharyngitis. The
clinical manifestation of the response and
its severity in an individual is determined
by host genetic susceptibility, the
virulence of the infecting pathogen and a
conducive environment.
• RF is thought to occur only after GAS
infection of the upper respiratory tract
although this thinking has been
challenged by those working in tropical
areas where skin infections are rife.
166
ACUTE RHEUMATIC FEVER
• The clinical presentation can be
vague and difficult to diagnose.
• Currently the modified DuckettJones criteria form the basis of
the diagnosis of the condition.
167
• It is thought that 0.3-30% of untreated
group A beta haemolytic streptococcal
infection progress to develop acute
rheumatic fever.
168
Carapetis. Lancet 2005;366:155
169
170
RHEUMATIC HEART
DISEASE
• Rheumatic Heart Disease is the
permanent heart valve damage
resulting from one or more
attacks of ARF.
• It is thought that 40-60% of
patients with ARF will go on to
developing RHD.
171
RHEUMATIC HEART
DISEASE
• The commonest valves affecting
are the mitral and aortic, in that
order. However all four valves
can be affected.
172
RHEUMATIC HEART
DISEASE
• Sadly, RHD can go undetected
with the result that patients
present with debilitating heart
failure.
• At this stage surgery is the only
possible treatment option.
173
RHEUMATIC HEART
DISEASE
• Patients living in poor countries
have limited or no access to
expensive heart surgery.
• Prosthetic valves themselves
are costly and associated with
a not insignificant morbidity and
mortality.
174
RHEUMATIC FEVER IS
PREVENTABLE
Costa Rica
Cuba
175
The main content of the activities
focused around early detection and
treatment of sore throats and
streptococcal pharyngitis.
The project also included primary and
secondary prevention of RF/RHD,
training of personnel, health education,
dissemination of information,
community involvement and
epidemiological surveillance.
176
There was a progressive decline in the
occurrence and severity of acute RF and
RHD, with a marked decrease in the
prevalence of RHD in school children.
A marked and progressive decline was
also seen in the incidence and severity of
ARF.
There was an even more marked reduction
in recurrent attacks of RF as well as in the
number and severity of patients requiring
hospitalization and surgical care.
177
What are the
clinical features
of strep sore
throat?
178
179
180
Hallmarks of STREP
sore throat
•
•
•
•
•
•
Tender lymph nodes
Close contact with infected person
Scarlet fever rash
Excoriated nares( crusted lesions) in infants
Tonsillar exudates in older children
Abdominal pain
• GOLD STANDARD: POSITIVE THROAT
CULTURE
181
Hallmarks of VIRAL
sore throat
•
•
•
•
•
•
•
Coryza: runny nose or mouth ulcers
Other family with COLD symptoms
Evidence of another viral infection
Itchy watery eyes
Hoarseness and cough: non-specific
Fever: not specific
Red Throat: not specific
182
What are the
treatment
regimens of
streptococcal
sore throat?
183
Primary Prevention of
Rheumatic Fever by
treating sore throat
Antibiotic
Administration
Dose
Benzathine
benzyl penicillin
Single IM injection
1.2 MU > 30kg
600 000 U < 30 kg
Phenoxymethyl
penicillin
(Pen VK)
PO for 10 days
250-500mg qds for 10 days
125mg qds X 10 if <30 kg
Erythromycin
ethylsuccinate
PO for 10 days
Use same dose as above.
Oral penicillin is less efficacious than Penicillin IMI
Anaphylaxis is extremely unusual
184